1. Field of the Invention
The present invention relates to a tissue implant for use in damaged load-bearing cartilaginous tissue, such as the meniscus and articular cartilage.
2. Related Art
Many non-calcified skeletal connective tissues such as articular cartilage, menisci, ligaments, tendons and intervertebral disc have a mechanical function and, as such, are subjected to dynamic mechanical loading during physiological activity. For example, joint forces are considerable during normal physiological activities and commonly exceed 2000 N or three times body weight and occur repetitively approximately 1 million times per year. Thus articular cartilage will be commonly subjected to contact stresses exceeding 5 MPa.
The cartilaginous tissues are composed of cells embedded within an extensive extracellular matrix. The functional behaviour of these tissues is best understood when it is considered as biphasic consisting of a fluid phase of interstitial water containing dissolved inorganic salts and a solid phase containing the collagen-proteoglycan organic solid matrix. The two phases together permit fluid flow through the permeable solid phase. It is the physicochemical interaction of the various components of the extracellular matrix which is responsible for the mechanical properties of the healthy tissues. For example in articular cartilage, there is a physico-chemical equilibrium between the osmotic swelling pressure (P.sub.swelling) of the proteoglycan gel which is balanced by the hydrostatic pressures (P.sub.elastic) due to the tensile stresses generated within the collagen fibre network. This balance exists even in unloaded articular cartilage. It is altered when the tissue is loaded in compression by an applied hydrostatic pressure (P.sub.applied) resulting in a net pressure differential (.DELTA.p) and fluid flow away from the compressed tissue. The appropriate equation is given by
.DELTA.p=P.sub.applied +(P.sub.elastic -P.sub.swelling)
This fluid flow will result in an increased proteoglycan concentration within the tissue and a change in the relative magnitudes of the stresses in the two solid components of articular cartilage. If the compressive load remains constant the rate of fluid flow decreases with time and eventually reduces to zero at a new state of equilibrium. This time-dependent creep behaviour is characteristic of all viscoelastic soft tissues.
The cells, although occupying less than 10% of the tissue volume, are necessary for the synthesis and maintenance of matrix levels and are, therefore, crucial to the structural integrity and function of the tissue. It is known that the cells, whether chondrocytes in cartilage, fibrochondrocytes in menisci, or tenocytes and fibroblasts in tendon and ligament respectively, are able to alter their metabolic activity in response to applied loads. Both the level of strain applied and the dynamic frequency are known to be important in determining this response. These processes are believed to be major factors in determining cellular activity in these tissues.
The mechanisms by which cells detect and respond to mechanical load are termed mechanotransduction pathways and are complex and poorly understood. mechanotransduction events may be resolved into extracellular components including cell deformation, hydrostatic pressures and streaming potentials, followed by intracellular signalling events such as intracellular calcium fluxes, cAMP production and cytoskeletal alterations which finally lead to altered effector cell response. However, understanding such mechanisms has been complicated by the need to investigate the processes at a number of different levels, including the cellular level.
Injuries to soft tissues are extremely common in hospital clinics. Indeed, soft tissue replacements amount to an estimated 35% of the world market for all medical devices (Materials Technology Foresight in Biomaterials, Institute of Materials, London (1995).
In the case of articular cartilage and knee menisci, traumatic damage is common in young active people. Natural repair is often poor due to limited vascularity. If untreated, damage commonly leads to progressive degenerative changes, such as osteoarthritis, in the injured tissue and associated structures. Current solutions, include the use of artificial joints but these implants have a relatively short lifespan of 12-15 years with subsequent replacements lasting for shorter periods. This is a special problem for patients who have received an implant early in life.
There have been many options proposed for the repair of soft tissues. These generally involve synthetic materials, biological materials or a combination of the two. The former solutions have the advantages of providing a structure which is immunologically acceptable and with the mechanical integrity required of load bearing structures. However their instability in the body leads to relatively poor long term performance. Biological solutions traditionally involve autografts, allografts or xenografts, depending on their source of tissues. Each of these options has proved to be far from ideal with, for example, autografts leading to donor site morbidity and allografts and xenografts leading to graft rejection.
Other common solutions involve augmentation devices incorporating both synthetic structures and biological grafts. These devices depend on tissue ingrowth and regeneration induced by the successful transfer of stress from the synthetic material to the natural tissues. This stress transfer process would need to change with time after implantation as the tissue regenerates. Clinical reports are not generally convincing due to, for example, the inadequate initial performance of the synthetic component of the augmentation device.
Commonly used procedures for treatment of articular cartilage lesions include the Pridie technique which involves drilling or abrasion of the joint surface to release repair cells which form a fibrocartilaginous repair tissue. Other procedures involve the use of carbon fibre rods or mats associated with drilling and the use of allografts and xenografts. These techniques lead to the formation of soft fibrocartilaginous tissue which has limited long-term stability. Options for the treatment of damaged menisci currently include, surgery to remove the damaged portion of meniscus (20 years ago, before the meniscus was better understood, damaged menisci were removed completely), implantation of a plastic meniscus or using fibrin-glue to glue back the torn portion of meniscus. However, in plastic meniscal implants the use of hydrogels is often inadequate and there are problems with shear/stress forces on the implant. The use of fibrin glue is also unsatisfactory because the meniscus still contains a point of weakness and is a non-homogeneous anisotropic structure.
The relative failure of many surgical, synthetic and graft solutions has led to the growing interest in the development of cell-seeded repair systems for solving a number of clinical problems related to connective tissues such as articular cartilage, menisci and ligaments. These systems have also been called tissue-engineered repair systems. Typically autologous or allogenic cells are isolated from a tissue biopsy removed from a site remote from the injury. The cells are expanded in cell culture and seeded in a suitable 3D resorbable scaffold material, which when implanted into the defective or damaged site elicit a biological repair.
There are some reports describing in vitro and in vivo evaluation of cell-engineered systems for repair of load-bearing cartilaginous tissues. Examples of such systems have been described by Brittberg et al (New England Journal of Medicine 331 889-95 (1994)), WO 89/00413, WO 90/09769, WO 91/16867, WO 90/12603, WO 95/31157 and Paige et al (Plastic and Reconstructive Surgery 97(1) 168-180 (1996)).
Brittberg et al describe a procedure in which autologous chondrocytes, expanded in culture, are transferred into the defect. This procedure does not involve a scaffold material and thus a periosteal graft is required, with associated donor site morbidity, to retain the cells within the defect. The implanted cells are denuded of matrix and therefore have no mechanical integrity on implantation. Also the technique is only suitable for lesions which do not include the sub-chondral bone.
Stone (WO 89/00413, WO 90/09769, WO 91/16867) describe prostheses for the intervertebral disc, meniscus or other similar tissue. Each prosthesis is said to include a dry, porous, volume matrix of biocompatible and bioresorbable fibres. These are described as being interspersed with glycosaminoglycan molecules, which may provide attachment sites for cross-links to the fibres. The shape of such devices can either be manufactured to replicate the outer surface contour of the biological structure which it is designed to replace, or can be manufactured to a larger shape and trimmed down to size. For long term in vivo performance, these prostheses require the infiltration of functional fibrochondrocytes to provide a scaffold for the regenerating tissue structure. However, this prosthesis is not cell seeded and thus does not depend upon the use of seeded cells into the scaffold prior to implantation. Additionally, the nature of the mechanical interaction has not been specified.
The choice of biomaterials has to date been largely empirical based on biocompatibility and the maintenance of cell morphology and function. Additionally, the structural design of devices has been generally ignored. Materials such as collagen in various forms, poly-1-lactic acid and alginates have been employed. Most of the post implantation analysis has involved histological and biochemical analysis of repair tissue, with only a few reports assessing its mechanical integrity. The mechanical integrity of the device pre-implantation has been largely ignored. For example, Vacanti (WO 90/12603) and Kim et al (Plastic and Reconstructive Surgery 94(2) 233-237 (1994)) describe a method in which chondrocytes are seeded onto a bioresorbable polymer scaffold for transfer into a cartilaginous defect. Whilst the constructs may have a defined shape and size, the mechanical properties do not approach that of articular cartilage. The compressive modulus of articular cartilage is approximately 5-10 MPa. Problems associated with ensuring an initial even cell density and maintenance of chondrocytes phenotype are not addressed. The application of a coating to the scaffold was proposed but only to induce cell attachment. The method relies upon the synthesis of sufficient cartilaginous matrix to fill voids within the scaffold before any significant mechanical integrity is achieved.
Paige et al (Plastic and Reconstructive Surgery 97(1) 168-180 (1996)) propose the use of cells embedded in alginate alone. However, these devices are approximately one hundred times less stiff than cartilage raising questions about the mechanical functionality of the device.
WO 95/31157 relates to an anatomically specific bioresorbable device for healing of voids in soft tissues, such as in articular cartilage and the associated subchondral bone. The device is described as being an internal three-dimensional structure in fibrous form, termed the macrostructure, with voids which are partially or totally filled with a polymer gel, forming a microstructure. The gel provides a carrier material for selected chondrocytes and in conjunction with chemical mediators into the cartilage region of the device to enhance tissue regeneration. The gel phase is designed to be resorbed after 72 hours in vivo. This prosthesis, therefore, only depends upon the seeded microstructure to deliver the cells and to enable the short term transfer of cells on to the fibrous scaffold. The design does not depend upon the total filling of the voids by the microstructure. There is no consideration or mention of the physicochemical interaction of the macrostructure and the microstructure or the resulting mechanical integrity of the prosthesis at any time following implantation.
None of the aforementioned methods will produce a construct with a mechanical function which resembles that possessed by the tissues to be repaired. In addition none of the aforementioned methods address the transfer of mechanical load to cells within the device leading to mechanotransduction-induced desired cell response. It has now been discovered that an approach which considers both the mechanical and biological aspects of implants for repair of damaged load-bearing connective tissue can provide a superior device for implantation.